Thys, A. | bioRxiv Science

bioRxiv2020

Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB

The adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex. This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate, and has been linked to the regulation of the NF-κB pathway downstream most immunoreceptors, inflammation and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine in position 165 in lymphoblastoid cells, and can be further induced following antigen receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark is dispensable for the generation of linear ubiquitin chains. However, phosphorylation allows the optimal activation of NF-κB in response to TNFα and T-cell receptor engagement. These results identify a new layer of regulation of the LUBAC, and unveil new strategies to modulate its action.View Full Text

immunology↗

bioRxiv2019

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-{kappa}B activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impaired autophagic flux, and culminates in lysosomal-mediated death, concomitantly with mTOR inactivation and dispersion from lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.

cell biology↗